B lymphocyte stimulator (BLyS™) is a member of the tumor necrosis factor (“TNF”) superfamily that induces both in vivo and in vitro B cell proliferation and differentiation (Moore et al., Science, 285: 260-263 (1999)). B lymphocyte stimulator is distinguishable from other B cell growth and differentiation factors such as IL-2, IL-4, IL-5, IL-6, IL-7, IL-13, IL-15, CD40L, or CD27L (CD70) by its monocyte-specific gene and protein expression pattern and its specific receptor distribution and biological activity on B lymphocytes. B lymphocyte stimulator expression is not detected on natural killer (“NK”) cells, T cells or B cells, but is restricted to cells of myeloid origin. B lymphocyte stimulator expression on resting monocytes is upregulated by interferon-gamma (IFN-gamma). The gene encoding B lymphocyte stimulator has been mapped to chromosome 13q34.
B lymphocyte stimulator is expressed as a 285 amino acid type II membrane-bound polypeptide and a soluble 152 amino acid polypeptide (Moore et al., 1999, supra). The membrane-bound form of B lymphocyte stimulator has a predicted transmembrane spanning domain between amino acid residues 47 and 73. The NH2-terminus of the soluble form of B lymphocyte stimulator begins at Ala134 of the membrane-bound form of B lymphocyte stimulator. Both the soluble and membrane-bound forms of the protein form homotrimers. Soluble recombinant B lymphocyte stimulator has been shown to induce in vitro proliferation of murine splenic B cells and to bind to a cell-surface receptor on these cells (Moore et al., 1999, supra). Soluble B lymphocyte stimulator administration to mice has been shown to result in an increase in the proportion of CD45Rdull, Ly6Dbright (also known as ThB) B cells and an increase in serum IgM and IgA levels (Moore et al., 1999, supra). Thus, B lymphocyte stimulator displays a B cell tropism in both its receptor distribution and biological activity.
Based on its expression pattern and biological activity, B lymphocyte stimulator has been suggested to be involved in the exchange of signals between B cells and monocytes or their differentiated progeny. The restricted expression patterns of B lymphocyte stimulator receptor and ligand suggest that B lymphocyte stimulator may function as a regulator of T cell-independent responses in a manner analogous to that of CD40 and CD40L in T cell-dependent antigen activation.
Accordingly, molecules that specifically bind B lymphocyte stimulator would find a variety of uses in the study of the B lymphocyte stimulator cytokine, in the manufacture and purification of B lymphocyte stimulator in commercial and medically pure quantities, and in the development new therapeutic or diagnostic reagents. B lymphocyte stimulator binding polypeptides may also find medical utility in, for example, the treatment of B cell and/or monocyte disorders associated with autoimmunity, neoplasia, or immunodeficiency syndromes.